Design, Synthesis And Hypolipidemic Study Of Bromodomain Protein (BRD4) Inhibitors

Epigenetics has been defined as a genetic changes in the way of post-translational modifications that leads to the development of new phenotypes that are not encoded in DNA sequences.Studies have shown that the occurrence and progression of tumors,inflammation,and cardiovascular diseases are all related to the abnormal regulation of epigenetics.Posttranslational modifications(PTMs)of histones belong to the type of epigenetics,acetylation of lysine residues is a widely existing PTM,which regulates a variety of cellular processes.Abnormal histone acetylation can affect differentiation and apoptosis of cells,leading to multiple diseases.Bromodomain(BRD)is a protein domain that specifically recognizes acetylated lysine(KAc).In clinical research,BRD inhibitors have shown efficacy in anti-tumor,antiinflammatory and anti-cardiovascular diseases.In particular,BRD4 belong to Bromodomain and extraterminal domain(BET)family,as the target of epigenetics,is increasingly concerned by pharmaceutical companies and research institutes.At present,there are many types of lipid-lowering drugs that have been developed.Such as statin,cholesterol absorption inhibitors,phenoxyacetates(fibrates),and niacin etc.Statin drugs are effective in lowering LDL-C and triglyceride levels.The main effect of cholesterol absorption inhibitors is to lower LDL-C levels,and phenoxyacetates are significantly effective in lowering TG levels,niacin drugs can significantly increase HDL levels.The main content of this review is to design dual-activity hypolipidemic compounds based on BRD4 small molecule inhibitor RVX-208.RVX-208 is currently in clinical phase III.It is mainly used for the treatment of cardiovascular diseases and lowers the level of cholesterol(TC).The BRD4-based dual-activity hypolipidemic compounds use RVX-208 as the basic template,and introduces a phenoxyacetic acid at the end of the phenolic hydroxyl group that does not participate in protein binding to exert a TG lowering effect.This review mainly includes the following:1.The synthesis of RVX-208 and novel BRD4-based dual-activity hypolipidemic compounds RA-G and RB-G etc.2.To test the effect of the target compounds on the activity of BRD4 enzyme and on the level of apolipoprotein A-I and Apo A-I mRNA in human liver cells.